Hepatocellular carcinoma (HCC) is the second most deadly cancer with a <12% five-year survival rate and 8 month median survival. HCC incidence has tripled in the US over the past three decades. Of all major cancers in the US, HCC has shown the second and single greatest annual percent increase in incidence and mortality, respectively. Racial/ethnic differences in HCC incidence have been consistently observed with excess rates seen among Asians/Pacific Islanders, Hispanics and African Americans. Inter-ethnic differences in the prevalence of known HCC risk factors (i.e. viral hepatitis infection and alcohol abuse) may explain the observed racial/ethnic differences in HCC incidence. However, taken together, these factors only account for half of disease burden in the US. Given that a large proportion of HCC remains unexplained, a study, especially in high-risk minority groups, to identify the etiologic factors for this fatal cancer is warranted. Obesity and type II diabetes, maor elements of metabolic syndrome, are highly prevalent in Hispanics and African Americans and suspected emerging risk factors for HCC. Their contribution to the rising HCC incidence in these populations is unknown. We propose a comprehensive analysis in a large, prospective and well- characterized Multiethnic Cohort Study (MEC) to identify factor(s) that explains racial/ethnic disparity in HCC risk, particularly the excess risk observed in Latinos and African Americans. The MEC is uniquely comprised of five racial/ethnic populations (>215,000 African Americans, Latinos, Japanese Americans, Native Hawaiians, and Caucasians) with varying HCC incidence rates. More than 800 incident cases of HCC have been diagnosed over a 19-year period (1993-2012) and comprehensive baseline and follow-up questionnaire data, clinical data, and pre-diagnostic blood samples have been collected in this cohort. The specific aims are: 1) to determine whether racial/ethnic differences in HCC incidence can be explained by inter-ethnic differences in the distribution of known and putative HCC risk factors; 2) to examine whether the association between obesity and other key elements of metabolic syndrome and HCC risk differs across racial/ethnic groups, and whether the association(s) is modified by known HCC risk factors. The increasing incidence coupled with HCC's high fatality rate among minority groups constitutes an emerging major public health problem. The proposed study will be the first population-based prospective study of HCC that includes a substantial number of Latinos, African Americans, Asians and Caucasians. Identifying etiologic factors that explain racial/ethnic differences in HCC risk could greatly enhance the current understanding of the HCC etiology in the US, help explain why the incidence has been rising significantly in US Hispanics and African Americans and have a significant impact on the primary prevention of this fatal cancer. In addition, more effective screening could be developed leading to earlier diagnosis and better survival.